We propose expanding our existing Parkinson's disease, Environment and Genes (PEG) study population to further investigate the contributions of specific agricultural pesticides alone and in combination with biologically relevant genes that increase susceptibility to Parkinson's disease (PD). With prior funding, we have already enrolled 363 movement disorder specialist-confirmed idiopathic PD patients and, by the end of 2010, have enrolled 910 population controls from a heavily pesticide exposed population in three rural counties of California's Central Valley. All PEG study participants provide a biologic sample, complete a risk factor interview that includes detailed pesticide/farm work exposure assessments, and provide lifetime residential and occupational addresses that are combined with California state mandated commercial pesticide use reports in our sophisticated geographic information system (GIS) computer model to estimate ambient pesticide exposure over time. Our specific aims in this application are (1) Establish the largest case-control study of well characterized incident Parkinson's disease in the US with unprecedented pesticide exposure assessment by recruiting 500 additional movement disorder specialist-confirmed incident cases of PD utilizing the California PD Registry - a unique and time-limited resource for PD research given that the financial situation of the state of California jeopardizes future state funding to continue this effort and the 2,600 patients already identified are aging and progressing rapidly with regard to disease state; (2) Create a novel, comprehensive tool to assess pesticide exposures by incorporating data on wind speed, direction, and atmospheric mixing heights, farm boundaries, and soil composition and groundwater flow; and expand and validate our existing GIS-based computer model of pesticide exposure by incorporating occupational addresses, in addition to residential addresses, to estimate exposure to commercial pesticides and validating our model using Dept of Pesticide Regulation and CA Air Resource Board water and air measurements; and (3) Investigate novel gene-pesticide interactions for recognized PD risk genes (PARK1/PARK4 SNCA, PARK2 parkin, PARK5 UCHL1, PARK6 PINK, PARK8 LRRK2, and PARK13 HTRA2). While the PEG study has provided important and groundbreaking first results on pesticide and pesticide-gene interactions in PD in humans, this application provides the opportunity to increase our sample size and therefore our statistical power to evaluate the impact of less commonly used pesticides, combinations of pesticides, less frequent genetic mutations, and GxE interactions with one of the best pesticide exposure assessment models in a well defined and extensively phenotyped case population. Improving our understanding of environmental toxins, the genetic variation, and their impact on idiopathic PD will improve prevention efforts, advance therapeutic developments, and inform public policy on pesticide regulation.